MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Several studies have tested whether use of substances can cause schizophrenia. However due to methodological limitations in the existing literature, uncertainties still remains. We aimed to investigate the association between several types of substance abuses and the risk of developing schizophrenia later in life. We did a nationwide, prospective cohort study using the detailed Danish registers, which enabled us to address some of the limitations from prior findings. Our cohort consisted of more than 3.13 mio. individuals, that we were able to follow up for more than 104 mio. years at risk. We found that dealing with a substance abuse increased the overall risk of developing schizophrenia by 6 times, with abuse of cannabis and alcohol presenting the highest associations (5 and 3 times increased risk). The risk was found to be significant even 10-15 years prior to a diagnosis of substance abuse.

Response: We knew that children born to parents with mental illness had an increased risk for developing a mental disorder them selves, either the same disorder as their parent or another menal disorder. We also knew that some of these children would have pootrt motor function and other difficulties in functioning. However previous studies were smaller, they were not based on a representative sample, and children were at different age. That is the background for The Danish High Risk and Resilience Study-VIA 7, in which a large group of 522 children and their families were thoroughly assessed. The children were seven year old, and 202 had a parent who had schizophrenia, 120 had a parent with bipolar disorder and 200 had parent with neither of these disorders.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a complex neuropsychiatric illness and multiple genetic risk factors contribute to the disease. However, it is unclear how these genetic risk factors act and which molecular functions are affected in brain cells of patients with schizophrenia. In this study, we used neurons derived from pluripotent stem cells of patients with schizophrenia and control samples with no history of neuropsychiatric disease. We identified changes related to the way DNA transcribes (a.k.a. gene expression) in schizophrenia compared to controls during activation of the neurons.

These changes affect genes that have been genetically associated with schizophrenia. Our study provides evidence that multiple genetic risk factors might lead to schizophrenia because of a damaging effect on the activity of neurons.

Antony Loebel, M.D.
Executive Vice President and Chief Medical Officer
Sunovion
Head of Global Clinical Development
Sumitomo Dainippon Pharma Group

MedicalResearch.com: What is the background for this study?

Response: Lurasidone hydrochloride (HCl) is an atypical antipsychotic approved by the FDA for the treatment of schizophrenia in 2010. There are a number of publications on lurasidone studies, pooled data that were included in a network meta-analysis of RCTs in schizophrenia. The meta-analysis compares lurasidone with other antipsychotics using RCTs where both medications were studied at the same time. Such approach (meta-analysis of similarly designed trials) allows for a state of the art review of efficacy, safety and tolerability of medications where direct head-to-head trials are not available.

Response: We deployed a mobile phone intervention called FOCUS as part of a larger multi-component effort called Improving Care Reducing Costs (ICRC).

ICRC was the first technology-aided relapse prevention program of its kind for people with schizophrenia; a very exciting multi-state project funded by the Center for Medicare and Medicaid Innovation (CMMI) led by Dr. John Kane at the Zucker Hillside Hospital and a team of researchers from multiple institutions. Several other technological interventions were used in concert with mHealth, including a web intervention called Coping with Voices Developed by Dr. Jen Gottlieb and a Daily Support Website developed by Dr. Armando Rotondi. A truly multi-disciplinary effort designed to help prevent re-hospitalization in people with psychosis who were recently discharged from the hospital; this is a group that is at very high risk for relapse.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Schizophrenia is a complex psychiatric disorder and many patients are not able to achieve remission on the available treatments. There are clear sex differences in many aspects of the illness, which not only implicates a role for the sex hormone estrogen in schizophrenia, but also highlights the need for sex-specific treatments.

Our group has conducted many clinical trials using adjunctive estradiol treatment, with excellent improvement in psychotic symptoms- however, there can be physical side effects with longer term estradiol use. Raloxifene and other selective estrogen receptor modulators ( SERMs) – the so-called “brain estrogens”, with their more specific brain impacts and less body side effects – provide an option to use longer term estrogen in people with refractory schizophrenia. We conducted the first ever pilot study of raloxifene in 2010, and now present findings from a bigger study of adjunctive raloxifene treatment in schizophrenia.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Despite the lack of empirical evidence that antipsychotic polypharmacy produces greater outcomes to antipsychotic monotherapy, and that several clinical guidelines recommend against it, patients with a diagnosis of schizophrenia continue to being discharged on polypharmacy. Over the past few years, attempts have been made to lower the rate of antipsychotic polypharmacy throughout the country. Most of the existing literature on this topic are based on Medicaid claims data which exclude data for patients discharged from state psychiatric inpatient hospitals. Our study is very important because it is the first time that data on the use of antipsychotic medications are analyzed using a large sample of discharges from state psychiatric inpatient hospitals. These hospitals now have the opportunity to benchmark their antipsychotic medication use rate with national rates more accurately, and therefore, develop and implement performance improvement activities that are more precise. The study found that 12% of all discharges were prescribed two or more antipsychotic medications. Of those patients discharged on at least one antipsychotic medication, 18% were prescribed two or more antipsychotics. The study also found that patients with a schizophrenia diagnosis and an inpatient hospital stay of 3 months or longer are more likely of being discharged on polypharmacy, and that the main reason for this was to reduce patient’s symptoms. Antipsychotic polypharmacy affects nearly 10,000 patients with schizophrenia annually in state psychiatric inpatient hospitals.Continue reading →

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Merritt:Research has indicated that levels of one of the main chemicals in the brain, glutamate, may be abnormal in schizophrenia. Almost sixty studies have measured glutamate levels in schizophrenia, however the findings are inconsistent, and it is thought that changes in glutamate levels may vary with the length or the severity of illness. This study therefore analysed all the published reports of glutamate in schizophrenia.

The main findings are that, overall, schizophrenia is associated with elevated glutamate in several brain regions; namely the medial temporal cortex, the basal ganglia and the thalamus. These changes also differed with the stage of illness; in the medial frontal cortex, glutamate was increased in people at risk for developing schizophrenia, but not in people who had been diagnosed with schizophrenia for several years, whereas in the medial temporal lobe the opposite pattern was detected.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It is now well established that patients with schizophrenia show reduced thickness of brain’s grey matter in Magnetic Resonance Imaging studies, indicating either a developmental or an acquired deficit in the amount of brain tissue. Such reductions are seen both in treated and untreated patients, suggesting that current treatments do not reverse the process of tissue loss, if at all this is occurring in patients. We wanted to study if subtle increase in brain tissue also accompanied this reduction. We observed that across the group of 98 medicated patients, reduced thickness was consistently accompanied by subtle, but nevertheless noticeable increases in thickness. Such increases were more pronounced in those with a longer duration of illness.

Alan S. Brown, M.D., M.P.H.
Professor of Psychiatry and Epidemiology
Columbia University Medical Center
Director, Program in Birth Cohort Studies, Division of Epidemiology
New York State Psychiatric Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Brown: Smoking during pregnancy is a risk factor for several pregnancy-related outcomes including low birthweight and preterm birth. Evidence for a link with schizophrenia is scant. We analyzed a maternal biomarker of smoking called cotinine, a nicotine metabolite, in mothers of nearly 1,000 schizophrenia cases and 1,000 controls in a national birth cohort in Finland. We found that heavy smoking in pregnancy was related to a 38% increase in schizophrenia risk in offspring and that as cotinine levels increased even in the more moderate smokers risk of schizophrenia also increased.

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Severance: This research stems in part from anecdotal dialogues that we had with people with psychiatric disorders and their families, and repeatedly the issue of yeast infections came up. We found that Candida overgrowth was more prevalent in people with mental illness compared to those without psychiatric disorders and the patterns that we observed occurred in a surprisingly sex-specific manner. The levels of IgG antibodies directed against the Candida albicans were elevated in males with schizophrenia and bipolar disorder compared to controls. In females, there were no differences in antibody levels between these groups, but in women with mental illness who had high amounts of these antibodies, we found significant memory deficits compared to those without evidence of past infection.

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Malaspina: Although over one hundred single nucleotide variations in the human genetic code are associated with schizophrenia, using big data these account for a small portion of schizophrenia risk and most of them overlap with risks for other mental conditions.

In a completely different hypothesis generated approach, we focused on identifying rare or novel variations in genes that we earlier found had brand new disrupting mutations for cases with no family history compared to healthy parents.

Four or 5 cases were found with other rare sequences in 4 such influential genes. The respective groups of cases markedly differed in clinical presentations.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Malaspina: Within the umbrella diagnosis of Schizophrenia are separate diseases for which specific treatments can be developed. For these genes we identified groups with a developmental condition, early adult deterioration, one with specific working memory dysfunction and one with slow processing speed.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Malaspina: Removing the 30% of cases harboring one of these genes from the patient mix will allow faster progress on the other cases for person specific treatments.

MedicalResearch.com: Is there anything else you would like to add?

Dr. Malaspina: In humans as in other mammals, most new gene disruptions arise in the paternal germ line and are transmitted to young in association with paternal age. This replenishes psychosis genes into the population since persons with the disease have fewer offspring. Once these genes arise the can then be inherited and produce inherited forms of the disease.

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Potvin: Life expectancy is substantially reduced in schizophrenia, and one of the main factors contributing to this is the high prevalence of cigarette smoking in these patients. The leading hypothesis for cigarette smoking in schizophrenia is the self-medication hypothesis. Although some empirical results show that nicotine improves cognitive performance in schizophrenia, some authors have criticized the self-medication hypothesis for its implied (and unintented) justification of cigarette smoking in schizophrenia. About a decade ago, it has been hypothesized that cigarette smoking may be more reinforcing in schizophrenia patients, due to biological dysfunctions common to schizophrenia and tobacco use disorder. However, that model had not been formally tested.

Based on recent findings showing that cigarette cravings are increased in schizophrenia smokers, compared to smokers with no comorbid psychiatric disorder, we performed a neuroimaging study on cigarette cravings in schizophrenia. Unless we are wrong, this was most probably the first study to do so. We found that relative to control smokers, smokers with schizophrenia had increased activations of the ventro-medial prefrontal cortex in response to pleasant images of cigarette. What is is interesting is that the ventro-medial prefrontal cortex is one of the core regions of the brain reward system, which mediated the reinforcing effects of several psycho-active substances, including tobacco. As such, our results tend to confirm the assumption that cigarette might be more reinforcing in schizophrenia smokers.

S. Hong Lee, PhD
Queensland Brain Institute, The University of Queensland, Brisbane
School of Environmental and Rural Science, University of New England, Armidale
Australia

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Previous studies reported increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for schizophrenia tend to have children at an earlier or later age.

We found evidence for a significant overlap between genetic factors associated with risk of schizophrenia and genetic factors associated with Age at First Birth (AFB). We observed a U-shaped relationship between schizophrenia risk and maternal AFB, consistent with the previously reported relationship between schizophrenia risk in offspring and maternal age when not adjusted for age of the father.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The humanitarian crises in Europe, the Middle East, north Africa, and central Asia have led to more displaced people, asylum seekers, and refugees worldwide than at any time since the second world war. Refugees are known to be at an increased risk of mental health problems, such as post-traumatic stress disorder and other common mental disorders, compared to non-refugee migrants, but little is known about their risk of psychosis.

The aim of the study was to determine the risk of schizophrenia and other non-affective psychotic disorders among refugees, compared to non-refugee migrants, and the general Swedish population. We used a linked national register data to examine more than 1.3 million people in Sweden, and tracked diagnoses of non-affective psychotic disorders among the population. The cohort included people born to two Swedish-born parents, refugees, and non-refugee migrants from the four major refugee generating regions: the Middle East and north Africa, sub-Saharan Africa, Asia, Eastern Europe and Russia.

Results showed 3,704 cases of non-affective psychotic disorders during the 8.9 million person years of follow up. Refugees granted asylum were on average 66% more likely to develop schizophrenia or another non-affective psychotic disorder than non-refugee migrants. In addition, they were up to 3.6 times more likely to do so than the Swedish-born population. Incidence rates for non-affective psychosis were 385 per million in those born in Sweden, 804 per million in non-refugee migrants, and 1264 per million in refugees.

The increased rate in refugees was significant for all areas of origin except sub-Saharan Africa, for whom rates in both groups were similarly high relative to the Swedish-born population. One possible explanation is that a larger proportion of sub-Saharan Africa immigrants will have been exposed to deleterious psychosocial adversities before emigration, irrespective of refugee status. Alternatively post-migratory factors, such as discrimination, racism, and social exclusion may explain these high rates.
Overall, our findings are consistent with the hypothesis that increased risk of non-affective psychotic disorders among immigrants is due to a higher frequency of exposure to social adversity before migration, including the effects of war, violence, or persecution.

MedicalResearch.com Interview with:
Theresa WimberleyPhD studentNational Centre for Register-based Research
School of Business and Social Sciences
Aarhus University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Approximately 30% of patients with schizophrenia suffer from treatment-resistant schizophrenia, i.e. they do not respond to first-line antipsychotic treatment. Identification of high-risk patients as early as possible is crucial in order to optimize treatment and improve prognosis. In a large population-based cohort of patients diagnosed with schizophrenia we found the following candidate predictors of treatment resistance:

younger age at diagnosis,

living in less urban areas,

paranoid schizophrenia subtype,

a history of psychiatric hospital admission,

personality disorder,

suicide attempt, and

psychotropic drug use.

Additionally, as opposed to other studies using treatment-based proxies for treatment-resistant schizophrenia, this study not only considered clozapine users as treatment resistant. We extended the proxy definition to include patients eligible for clozapine, as clozapine is considered to be under-prescribed. We found similar results regardless of definition used.

Hannah J. Jones, PhD
Centre for Academic Mental Health, School of Social and Community Medicine,
Medical Research Council (MRC) Integrative Epidemiology Unit
University of Bristol, Bristol, England

MedicalResearch:What is the background for this study? What are the main findings?

Dr. Jones: Schizophrenia is a highly heritable condition characterised by relatively diverse symptoms and frequent comorbid disorders. However, at present we don’t know how genetic risk for schizophrenia is expressed in children/adolescents in the general population.

To investigate this, we studied data from individuals within the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort which consists of approximately 14,000 children born to women living in the former Avon Health Authority area in England with an expected delivery date from April 1, 1991, to December 31, 1992.

We used genetic data from approximately 5,000 ALSPAC children and measures from adolescence relating to psychopathology to determine whether genetic risk for schizophrenia is associated with variation in psychotic experiences (e.g. delusions, hallucinations), negative symptoms (e.g. apathy, withdrawal), depressive disorder and anxiety disorder during this developmental period.

We derived a score of genetic risk for schizophrenia in each individual within our study. This score is normally distributed such that most people have some genetic risk and a few people have very high or very low genetic risk.

We found very weak evidence of an association between genetic risk for schizophrenia and psychotic experiences in adolescence and no evidence of an association with depressive disorder. However, we found strong evidence of association between genetic risk for schizophrenia and negative symptoms and anxiety disorder.Continue reading →

Medical Research: What is the background for this study? What are the main findings?

Dr. Crandall: We wanted to investigate whether or not there were significant differences in the microbiome (microbial composition) of patients with schizophrenia versus controls. The other researchers have demonstrated a connection between microbiome diversity and brain development and behavior modulation associated with a variety of disorders. Our initial study focuses on the oropharyngeal as a target for the microbiome characterization, but we have additional work relating to other microbiomes (e.g., gut) for which we are still in the process of analyzing the data. Collected microbiome data from 16 individuals with schizophrenia and 16 controls (matched as best we could and corrected statistically for differences between the populations), we showed differences in the microbiome taxonomic diversity and functional diversity. Specifically, we identified a significant increase in the number of metabolic pathways related to metabolite transport systems; whereas, carbohydrate and lipid pathways and energy metabolism were abundant in controls.

Dr. Slifstein:There has been considerable basic and clinical neuroscience research showing that the neurotransmitter dopamine plays a role in tuning cognitive processes taking place in the cortex. It has long been thought that dopamine is involved in the cognitive difficulties experienced by patients with schizophrenia, but it has been challenging to study dopamine in the cortex and other parts of the brain except in a deep structure rich in this neurotransmitter and its receptors, the striatum. In our study, we used an experimental design with Positron Emission Tomography (PET) imaging that allowed us to infer the amount of dopamine in the cortex.

Medical Research: What is the background for this study? What are the main findings?

Dr. Furukawa: The efficacy of antidepressants in the treatment of depressive
disorders has recently been called into question as some studies
suggested they may have less efficacy for the milder spectrum of the
disorder. It is not known if the same would apply to antipsychotics,
which constitute the mainstay in the treatment of schizophrenia. We
found that, in patients with schizophrenia with acute treatment as
well as with predominant negative symptoms, the severer the baseline
severity, the greater the magnitude of the benefit from the active
treatment in comparison with placebo.Continue reading →

Dr. Konopaske: Using postmortem human brain tissue this study did reconstructions of basilar dendrites localized to pyramidal cells in the deep layer III of the dorsolateral prefrontal cortex. Tissue from individuals with schizophrenia, bipolar disorder or controls was examined. Dendritic spine density (number of spines per μm dendrite) was significantly reduced in bipolar disorder and also reduced in schizophrenia at a trend level. The number of dendritic spines per dendrite and dendrite length were significantly reduced in subjects with schizophrenia and bipolar disorder.

Dr. Correll: The main findings of the study of 398 patients with first-episode schizophrenia-spectrum disorders who were on average in their mid twenties are that:

1) despite their young age, an average of only 47 days lifetime antipsychotic exposure and overweight/obesity figures that were comparable to similarly aged US population members, there was a clear pattern of increased smoking and several metabolic risk parameters compared to similarly aged persons in the general US population;

2) dyslipidemia, a constellation of at least one relevant abnormal blood fat value, was as frequent as in a 15-20 years older general US population;

Dr. Meier: People with an obsessive-compulsive disorder are at a 6 to 7 times higher risk of developing schizophrenia than people without an obsessive-compulsive disorder. If the parents are diagnosed with an obsessive-compulsive disorder, their offspring experience a 3 to 4 times higher chance to develop schizophrenia.Continue reading →

Prof. Ettinger:We found that 24-hour sleep deprivation induced subjective cognitive, perceptual and emotional alterations resembling the symptoms of schizophrenia. We also observed that sleep deprivation led to a deficit in a sensorimotor filter mechanism called prepulse inhibition (PPI), similar to the disturbance seen in schizophrenia.Continue reading →

Dr. Nykjaer: It is well known that ADHD is a complex condition caused by a number of factors including genetic and environment. However, approximately 75% etiology is considered to be genetic and a large body of investigations suggests that it is multiple genes each with a moderate effect that is responsible for conferring susceptibility to ADHD. We have here found one single gene the dysfunction of which is sufficient to trigger the disease. The gene encodes a receptor, SorCS2, which ensures correct wiring our reward system during embryonic development. Malfunction of the receptor causes ADHD-like symptoms in mice. It is well accepted that ADHD predisposes to psychiatric disorders and genetic reports have linked variations in the SorCS2 gene with schizophrenia. Studies are currently ongoing to evaluate if mutations disrupting the function of SorCS2 may also result in schizophrenia. If this is the case we have come closer to an explanation for the link between ADHD and psychiatric disorders. In the future when prenatal genetic screening becomes established, non-sense mutations in the SorCS2 gene can be used to predict that the child will develop ADHD with 100% certainty. Continue reading →

MedicalResearch.com Interview with:Scott Stroup, MD, MPH
Professor of Psychiatry
Director, Program for Intervention Effectiveness Research,
Associate Director for Adult Services, Division of Mental Health Services and Policy Research, New York State Psychiatric InstituteDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York

MedicalResearch: What are the main findings of the study?

Dr. Stroup:We conducted a study sponsored by the National Institute of Mental Health that compared long-acting injectable antipsychotics for people with schizophrenia. Long-acting injectable antipsychotics, also known as depot antipsychotics, are used to promote treatment adherence. We compared a newer injectable antipsychotic, paliperidone palmitate, to an older one, haloperidol decanoate. We did not find an advantage for the newer drug in overall effectiveness. The drugs performed very similarly, and were tolerated about the same.Continue reading →

Professor Kulkarni: Persistent schizophrenia is difficult and unfortunately common, despite advances over the past years in antipsychotic drug development. New treatment approaches are urgently needed. Also, a specific focus for women with schizophrenia is still somewhat lacking and there is a need to consider the special issues facing women with schizophrenia.

Over many years, we have been conducting clinical trials to develop the role of adjunctive estradiol use to treat symptoms of schizophrenia. This study is the largest clinical trial in the world of this type and we found that in an 8 week, three arm, double blind, placebo-controlled, adjunctive trial of transdermal estradiol (200mcg v 100mcg v placebo) in 183 women with schizophrenia, that the women who received either 200mcg or 100mcg transdermal estradiol made a better recovery. The women who received 200mcg transdermal estradiol made a slightly better recovery than women receiving 100mcg transdermal estradiol. Both estradiol groups were significantly better than the group who received adjunctive transdermal placebo.

In the current online issue of PLoS ONE, researchers at the University of California, San Diego School of Medicine say they have identified a set of laboratory-based biomarkers that can be useful for understanding brain-based abnormalities in schizophrenia. The measurements, known as endophenotypes, could ultimately be a boon to clinicians who sometimes struggle to recognize and treat the complex and confounding mental disorder.

“A major problem in psychiatry is that there are currently no laboratory tests that aid in diagnosis, guide treatment decisions or help predict treatment response or outcomes,” said Gregory A. Light, PhD, associate professor of psychiatry and the study’s first author. “Diagnoses are currently based on a clinician’s ability to make inferences about patients’ inner experiences.”

Diagnosing and treating schizophrenia is a particularly troubling challenge. The disorder, which affects about 1 percent of the U.S. population or roughly 3 million people, is characterized by a breakdown of normal thought processes and erratic, sometimes dangerous or harmful, behaviors.

“Schizophrenia is among the most severe and disabling conditions across all categories of medicine,” said Light, who also directs the Mental Illness, Research, Education and Clinical Center at the San Diego VA Healthcare System.

The precise cause or causes of schizophrenia are not known, though there is a clear genetic component, with the disorder more common in some families.

Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient’s inner experiences. That is, their ability to describe what’s happening inside their minds.

“But even the best clinicians struggle with diagnostic complexities based on sometimes fuzzy clinical phenomenology,” said Light. The clinical challenge is compounded by the fact that “many schizophrenia patients have cognitive and functional impairments,” said Light. They may not be able to reasonably explain how or what they think.

Light and colleagues investigated whether a select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable, accurate, long-term indicators of brain dysfunction, even when overt symptoms of the disorder were not apparent. These markers ranged from tests of attention and memory to physiological assessments of basic perceptual processes using scalp sensors to measure brain responses to simple sounds.

The researchers measured the biomarkers in 550 schizophrenia patients, and then re-tested 200 of the patients one year later. They found that most of the markers were significantly abnormal in schizophrenia patients, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient.

Light said further research is required, including whether the endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions or even be used to predict which subjects are at high risk of developing a psychotic illness.

“We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia,” Light said.

Knowledge about the biological origin of diseases like schizophrenia, bipolar disorder and other psychiatric conditions is critical to improving diagnosis and treatment.

In an effort to push the field forward, three UCLA researchers, along with scientists from more than 20 countries, have been taking part in one of the largest collaborative efforts in psychiatry — a genome-wide study involving more than 50,000 study participants aimed at identifying which genetic variants make people susceptible to psychiatric disease.

This collaborative, the Psychiatric Genome-Wide Association Study Consortium (PGC), now reports in the current online edition of the journal Nature Genetics that it has discovered that common genetic variants contribute to a person’s risk of schizophrenia and bipolar disorder.

The PGC’s studies provide new molecular evidence that 11 regions on the genome are strongly associated with these diseases, including six regions not previously observed. The researchers also found that several of these DNA variations contribute to both diseases.

The findings, the researchers say, represent a significant advance in understanding the causes of these chronic, severe and debilitating disorders.

The UCLA researchers who contributed to the schizophrenia study are Roel A. Ophoff, a professor of psychiatry and human genetics and one of the founding principal investigators of the schizophrenia portion of the study; Dr. Nelson Freimer, a professor of psychiatry and director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA; and Rita Cantor, a professor of psychiatry and human genetics.

Schizophrenia and bipolar disorder are common and often devastating brain disorders. Some of the most prominent symptoms of schizophrenia are persistent delusions, hallucinations and cognitive problems. Bipolar disorder is characterized by severe, episodic mood swings. Both affect about 1 percent of the world’s population and usually strike in late adolescence or early adulthood.

Despite the availability of treatments, these illnesses are usually chronic, and patients’ response to treatment is often incomplete, leading to prolonged disability and personal suffering. Family history, which reflects genetic inheritance, is a strong risk factor for both schizophrenia and bipolar disorder, and it has generally been assumed that dozens of genes, along with environmental factors, contribute to disease risk.

In the schizophrenia study, a total of seven locations on the genome were implicated in the disease, five of which had not been identified before. When similar data from the bipolar disorder study, which ran concurrently, were combined with results from the schizophrenia study, three gene locations were identified that proved to be involved in both disorders, suggesting a “genetic overlap” between schizophrenia and bipolar disorder.

“Genetic factors play an important role in the susceptibility to develop schizophrenia,” Ophoff said, “but identifying these genetic factors has been very difficult. We know that schizophrenia is not caused by a single gene that explains everything but an interplay of many genetic and non-genetic factors.”

At the same time, he said, the disease itself is not uniform but manifests itself in different ways; currently, there is no objective biological marker or “sign” that can be used for diagnosis.

“This so-called heterogeneity at the genetic and clinical level is the biggest challenge for genetic studies of neuropsychiatric disorders,” Ophoff said. “One way to deal with these difficulties is to increase the size of the study so there is sufficient ‘power’ to detect genetic effects, even amidst this clinical and genetic diversity.”

The fact that even this large study resulted in a limited number of schizophrenia and bipolar genes demonstrates once again, he said, the complex nature of the disease.

The research was funded by numerous European, American and Australian funding bodies. Funds for coordination of the consortium were provided by the National Institute of Mental Health in the U.S.

Columbia University Medical Center researchers have shown that new, or “de novo,” protein-altering mutations—genetic errors that are present in patients but not in their parents—play a role in more than 50 percent of “sporadic” —i.e., not hereditary—cases of schizophrenia. The findings will be published online on August 7, 2011, in Nature Genetics.

A group led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhD, examined the genomes of patients with schizophrenia and their families, as well as healthy control groups. All were from the genetically isolated, European-descent Afrikaner population of South Africa.

These findings build on earlier studies by Karayiorgou, professor of psychiatry at Columbia University Medical Center. More than 15 years ago, Karayiorgou and her colleagues described a rare de novo mutation that accounts for 1-2 percent of sporadic cases of schizophrenia. With advances in technology, three years ago the Columbia team was able to search the entire genome for similar lesions that insert or remove small chunks of DNA. The mutations found accounted for about 10 percent of sporadic cases.

Encouraged by their progress, they wondered whether other, previously undetectable, de novo mutations accounted for an even greater percentage of sporadic cases. Using state-of-the-art “deep sequencing,” they examined the nucleotide bases of almost all the genes in the human genome. This time they found 40 mutations, all from different genes and most of them protein-altering. The results point the way to finding more, perhaps even hundreds, of mutations that contribute to the genetics of schizophrenia—a necessary step toward understanding how the disease develops.

“Identification of these damaging de novo mutations has fundamentally transformed our understanding of the genetic basis of schizophrenia,” says Bin Xu, PhD, assistant professor of clinical neurobiology at Columbia University Medical Center and first author of the study.

“The fact that the mutations are all from different genes,” says Karayiorgou, “is particularly fascinating. It suggests that many more mutations than we suspected may contribute to schizophrenia. This is probably because of the complexity of the neural circuits that are affected by the disease; many genes are needed for their development and function.” Karayiorgou and her team will now search for recurring mutations, which may provide definitive evidence that any specific mutation contributes to schizophrenia.

The potentially large number of mutations makes a gene-therapy approach to treating schizophrenia unlikely. Researchers suspect, however, that all of the mutations affect the same neural circuitry mechanisms. “Using innovative neuroscience methods,” says co-author Dr. Joseph Gogos, MD, PhD, and associate professor of physiology and neuroscience at Columbia University Medical Center, “we hope to identify those neural circuit dysfunctions, so we can target them for drug development.”

The study’s results also help to explain two puzzles: the persistence of schizophrenia, despite the fact that those with the disease do not tend to pass down their mutations through children; and the high global incidence of the disease, despite large environmental variations.

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